when ..GAT gta..//..cag TCA.. changes to ..GA_ gta..//..cag TCA.., based on a coding DNA reference sequence the variant is described as LRG_199t1:c.3921del (NC_000023.10:g.32459297del) and not as c.3922del (which would translate to g.32456507del)

Examples

one nucleotide - NG_012232.1:g.19del

a deletion of the T at position g.19 in the sequence AGAATCACA to AGAA_CACA

NOTE: it is allowed to describe the variant as NG_012232.1:g.19delT

several nucleotides

NG_012232.1:g.19_21del

a deletion of nucleotides g.19 to g.21 in the sequence AGAATCACA to AGAA___CA

NOTE: it is allowed to describe the variant as NG_012232.1:g.19_21delTCA

the deletion of the T nucleotide at the exon/exon border in the sequence ..GAT gta..//..cag TCA.. changing to ..GA_ gta..//..cag TCA..

NOTE : according to an exception of the 3’rule the variant (NC_000023.10:g.32459297del) is not described as c.3922del since this would shift the position of the variant to the next exon (c. 3922 linking to g.32456507) (see exception in Numbering and see Q&A)

exon/intron

LRG_199t1:c.1704+1del

the deletion of the G nucleotide at the exon/intron border in the sequence GAACAGgt…/..agTGCCTT changing to GAACAG_t…/..agTGCCTT (not c.1704del)

NOTE: this description does not depend on the effect observed on RNA level, giving either altered splicing or r.1704del

intron/exon

LRG_199t1:c.1813del

the deletion of the G nucleotide at the intron/exon border in the sequence CTGGCCgt…/..agGTTTTA changing to CTGGCCgt…/..ag_TTTTA (not c.1813-1del)

NOTE: this description does not depend on the effect observed on RNA level, giving either altered splicing or r.1813del

exons

NG_012232.1(NM_004006.1):c.4072-1234_5155-246del

a deletion of nucleotides c.4072-1234 to c.5155-246 removing exon 30 (starting at position c.4072) to exon 36 (ending at position c.5154) of the DMD-gene.

NOTE : c.4072-1234_5155-246delXXXXX, the size of the deletion (XXXXX) should not be described

NG_012232.1(NM_004006.1):c.(4071+1_4072-1)_(5154+1_5155-1)del

a deletion of exon 30 (starting at position c.4072) to exon 36 (ending at position c.5154) of the DMD-gene. The deletion break point has not been sequenced. Exons 29 (ending at c.4071) and 37 (starting at nucleotide c.5155) have been tested an shown to be not deleted. The deletion therefore starts in intron 29 (position c.4071+1 to c.4072-1) and ends in intron 36 (position c.5154+1 to c.5155-1).

NOTE : as mentioned (Uncertain) the description can also be probe-based. For a deletion of exons 30 to 36, detected using MLPA, the description would be NG_012232.1(NM_004006.1):c.(3996_4196)_(5090_5284)del, i.e. following the suggestion to use the central position (3’ nucleotide) of the probe ligation site. E.g. the MLPA exon 29 probes hybdrize from position c.3963 to c.4030 giving c.3996 as the position to use in the description.

NOTE : previously, the suggestion was made to describe such deletions using the format NG_012232.1(NM_004006.1):c.4072-?_5154+?del. However, since c.4072-? indicates “to an unknown postion 5’ of c.4072” and c.5154+? “to an unknown postion 3’ of c.5154” this description is not correct when it is known that exons 29 and 37 are present. See also SVD-WG003 (undecided).

LRG_199t1:c.720_991del

a deletion of nucleotides c.720 to c.991 starting in exon 8 (position c.720) and ending in exon 10 (position c.991) of the DMD-gene.

NOTE : the description NM_\004006.2:c.720991del is not correct, the reference sequence NM\004006.2 is a coding DNA reference sequence which does not include the intron sequences involved

NG_012232.1(NM_004006.1):c.(?_-245)_(31+1_32-1)del

a deletion starting somewhere upstream of a gene, last postion tested postive c.-244, and ending in the intron between nucleotides c.31+1 and c.32-1 (intron 1).

gene

NC_000023.11:g.(31060227_31100351)_(33274278_33417151)del

a deletion of the entire DMD gene based on a SNP-array analysis where the maximum size of the deletion lies between SNPs rs396303 and rs7887548 (nucleotides 31060227 and 33417151) and the minimum size between SNPs rs808178 and rs7887103 (nucleotides 31100351 and 33274278). Based on a coding DNA reference sequence the deletion can be best described as c.0 (using NC_000023.11(NM_004006.2):c.(-205839_-62966)_(*21568_*61692)del makes no sense).

NC_000023.11:g.(?_31120496)_(33339477_?)del

a deletion of the entire DMD gene based on a MLPA assay where nucleotides g.31120496 and g.33339477 are the center of the probes for the resp. last and first (brain promoter) exons. Based on a coding DNA reference sequence the deletion can be described as c.0 or NC_000023.11(NM_000109.3):c.(?_-212)_(*1423_?)del.

NG_012232.1:g.19_21=/del

a mosaic case where from position g.19 to g.21 besides the normal sequence also chromosomes are found containing a deletion of this sequence

NG_012232.1:g.19_21=//del

a chimeric case, i.e. the sample is a mix of cells containing g.19_21= and g.19_21del

Q&A

Can I use NG_012232.1:g.123del6 to describe a 6 nucleotide deletion?

No, a deletion of more than one residue should mention the first and last residue deleted, separated using the range symbol ("_", underscore), e.g. NG_012232.1:g.123_128del and not NG_012232.1:g.123del6.

In the example above, LRG_199t1:c.3921del, should the description based on a coding DNA reference sequence not be LRG_199t1:c.3922del?

Strictly speaking you are right. However, for cases like this an exception was made to prevent that when c.3922del is translated back to a genomic position one would end up at the wrong nucleotide in the wrong exon (NC_000023.10:g.32456507del in stead of NC_000023.10:g.32459297del).

Is the description of a deletion of exon 17 as c.EX17del still allowed?

A description like c.EX17del has never been allowed. Descriptions should be specific and indicate the nucleotides affected by the change.

Deletions in the BRCA1 gene are usually mediated by Alu sequences having a very high homology, reaching 100% in the breakpoint region. In such cases, what nucleotide should be used to describe the deletion breakpoint?

In cases like this the 3'rule applies (see Recommendations General), i.e. the deletion breakpoint is determined by the first nucleotide that differs after shifting the alignment as far 3' as possible. The first nucleotide differing is the first nucleotide deleted.

PCR analysis of a gene on the X-chromosome shows products for exons 1_3, no product is detected for exons 4_14 (exon 14 is the last exon of the gene). Since PCR fails already when one primer is not hybridising, we are not sure whether exon 4 and 14 are completely absent, or only partially. To describe the deletion I would therefore like to use the last base of exon 3 with "+?" and the last base of exon 13 with a "+?. What are your recommendations? (Erik-Jan Kamsteeg, Nijmegen, Nederland)

Literally speaking you are right and it is best to set the borders as precise as possible. When exon 3 is present the location of the reverse primer can be used to set the most 5' border (something like c.987+123). However, for the 3' end your reasoning does not make a difference. Since you do not know how far the deletion extends, you have no positive PCR limiting the deletion at the 3' end, using the location of exon 13 since exon 14 might be present would give the wrong impression. Consequently the precise description can only be like c.(987+123_?)del. Is this realy more informative then c.(987+1_?)del, using the exon 3 exon/intron border?

In literature I often see the description "deltaF508" for a variant in the CFTR gene in patients with Cystic Fibrosis. Is the variant detected in these patients NM_000492.3:c.1522_1524delTTT?

No. The sequence surrounding amino acid Phe508 in the CFTR gene is ..-ATC-TTT-GGT-.. (c.1519 to c.1527). Three different deletions (TC-T, C-TT and -TTT-) would give the reported protein variant "Phe508del". Applying the 3' rule [_see Recommendations_](/recommendations/general/) yields two different changes at DNA level, NM_000492.3:c.1521_1523del and NM_000492.3:c.1522_1524del. When you assume the change at DNA level is c.1522_1524delTTT, deletion of exactly the Phe508 encoding triplet, you are wrong. The change found in patients is mostly NM_000492.3:c.1521_1523delCTT. So, without a proper description in the manuscript one can not be certain.

Suggest to use "los" for a loss from a mononucleotide stretch

Pat O'Neill (Burlington, USA) writes; I especially like the use of "dup" in place of "ins" when the insertion creates a run of two or more nucleotides. I feel that there should be a parallel term for the loss of a nucleotide from a run of two or more instead of just "del". This is because of the mechanistic implications of both an ins and a del of a nucleotide in a run. Has this been discussed? My thought for a term in place of "del" is "los"for loss.Shuji Ogino (Boston, USA) agrees but suggests to use "dec" for a decrease in length.Reply (JdD); The "dup" nomenclature was introduced because it is simpler, shorter and less confusing (see above). The potential mechanistic relation is nice but was not decisive. Basically a description should be clear/unequivocal and it is not intended to contain other information.

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Discussions regarding HGVS nomenclature are necessary in order to further improve them. What is listed on these pages represents the current consensus of the recommendations. We invite everybody to send us comments or examples of cases that are not yet covered, with a suggestion of how to describe these (E-mail:VarNomen @ HGVS.org).